While the regulatory effects of CHRNA5 SNPs have mainly centered on PFC, widely recognized for its involvement in addiction [3, 54], noncoding SNPs nearby genes identified in more recent GWAS analyses have highlighted gene regulatory effects in unexpected brain tissues. The CHRNA4 splice site acceptor SNP rs2273500 (Table 1) was indicated as a cis-eQTL SNP for CHRNA4 in intralobular white matter [21]. The DNMT3B intronic SNP rs910083 (Table 1) [26] and CHRNA2 upstream SNP rs117804171, discovered for its association with lung cancer but then extended to smoking [34], were each indicated as cis-eQTL SNPs for their proximal gene in cerebellum, which has been often overlooked despite evidence for its involvement in the neurobiology of addiction [55–57]. Follow-up of these and other GWAS discoveries for functional or regulatory effects, in normal physiological vs. smoking-exposed states, is needed across the wide array of human brain tissues to expand our neurobiological understanding of initiating smoking, becoming a regular smoker, developing nicotine dependence, and ultimately improving cessation treatment strategies.
